Interlocking couplings for osmotic delivery devices

ABSTRACT

A delivery system is disclosed for delivering a fluid-sensitive active agent such as a somatotropin, or an analogue or derivative thereof, to an animal such as a bovine. The delivery system comprises a first wall section, a second wall section and a locking coupling therebetween. The coupled wall sections define a compartment, enclosing an active agent and an expandable driving member. Various embodiments of the locking coupling are disclosed.

This application is a continuation of application Ser. No. 08/485,877,filed Jun. 7, 1995, now U.S. Pat. No. 5,731,001.

TECHNICAL FIELD

This invention pertains to both a novel and to an unobvious deliverysystem. Particularly, the invention relates to a delivery system thatoperates by osmosis and more particularly, the invention relates to adevice that protects and administers a fluid-sensitive beneficial agentto a fluid environment.

BACKGROUND ART

Delivery devices for administering a beneficial agent to a biological,fluid environment of use are known to the prior art. See, for example,U.S. Pat. Nos. 5,137,727; U.S. Pat. No. 5,174,999; and 5,238,687.

These devices comprise a housing including fluid-impermeable first wallsection and a fluid permeable second wall section. An active agent isenclosed within the first wall section. An expandable driving member isenclosed within the second wall section. A partition member is betweenthe beneficial agent and the expandable driving member. An exitpassageway is formed in the fluid impermeable first wall section. Asfluid is imbibed through the fluid permeable second wall section, thedriving member expands within the second wall section, pushing thepartition member which forces the active agent through the exitpassageway.

The delivery devices described in the above patents operate successfullyfor their intended use and they can deliver many beneficial agents fortheir intended effects. Now, it has been observed that their use can belimited because difficulties associated with shortening the start-uptime for delivering the active agents from the device.

Implanted devices are continually exposed to biological fluids naturallypresent in the body. Fluids are imbibed across the fluid permeable wallsections containing the expandable driving member. When the partitionlayer or expandable driving member has occupied the entire volumedefined within the first and second wall sections, the expandabledriving member continues to expand. Pressure may accumulate within thedevice until it is sufficient to force a separation of the first wallsection from the second wall section. Thus there is a need for adelivery device that is essentially free of the problems associated withthe prior art and that, if such an implantable delivery device isprovided, it would have a practical application in the fields of humanand veterinary medicine particularly in the breeding and management offarm animals.

DISCLOSURE OF THE INVENTION

The present invention is directed to a fluid-imbibing delivery device ordispenser for storing and protecting a fluid-sensitive active agent andfor dispensing the agent to a fluid environment of use over a prolongedperiod of time.

In accordance with another aspect of the present invention, a deliverydevice having a fluid permeable wall section and a fluid impermeablewall section includes a locking coupling between the fluid permeablewall section and the impermeable wall section to provide additionalstrength to the joint between the two wall sections.

In accordance with another aspect of this invention, a delivery devicefor storing and protecting an active agent and for dispensing the activeagent to an environment of use includes a locking joint between thefirst and second wall portions of the delivery device. At least one ofthe wall sections has a mechanical rigidity greater than a wall sectioncomprising 85% cellulose acetate butyrate and 15% tributylcitrate . Alocking coupling between the first and second wall sections strengthensthe joint between the two sections.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawing figures, which are not drawn to scale, but are set forthto illustrate various embodiments of the invention, the drawing figuresare as follows:

FIG. 1 is a cross-sectional view of one embodiment of the deliverydevice of the invention, illustrating one structural embodiment of thedelivery system comprising a first walled section and a second walledsection.

FIG. 2 is an enlarged cross-sectional view of the locking couplingbetween the first wall section and the second wall section of taken fromwithin the circle in FIG. 1.

FIG. 3 is an enlarged cross-sectional view of another embodiment of thelocking coupling of the FIG. 1.

FIG. 4 is an enlarged top view of another embodiment of the lockingcoupling of FIG. 1, taken along the lines A--A of FIG. 5.

FIG. 5 is an enlarged, cross-sectional view of the still anotherembodiment of the locking coupling of FIG. 1.

FIG. 6 is an enlarged, fragmented cross-sectional view of anotherembodiment of the locking coupling of FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION

In the following discussion, like reference numerals refer to likeelements in the figures.

According to this invention, a locking coupling, as more fully describedlater in this application, strengthens the joint between the first andsecond wall sections. FIG. 1 illustrates one embodiment of the deliverydevice according to the present invention. Delivery system 10 of FIG. 1comprises a housing 11 formed of a wall 12, which wall comprises a firstwall section 12a and a second wall section 12b. Wall 12 encloses anddefines an internal compartment 18. Delivery system 10 has at least oneexit passageway 13 for delivering an active agent formulation 7 fromdelivery system 10.

Wall section 12a may be in the form of an tubular member having a firstand a second open ends 32 and 34, respectively. In this particularembodiment, an end cap 36 is positioned on first wall section 12a at itslead end 9. Either the wall section 12a or end cap 36 define thepassageway 13.

First wall section 12a encloses and defines the internal compartment 18initially occupied by the active agent 7. First wall section 12a alsocomprises a composition that is substantially impermeable to theexchange of fluid, active agent 7 and other ingredients contained indelivery system 10. The phrase substantially impermeable, as usedherein, indicates the volume of external fluid passing through the firstwall section 12a is substantially negligible, that is, about zero up toabout 1μ or up to about 1 ml/day. As a result, wall section 12a servesas a means for substantially protecting an active agent 7 that issensitive to exterior fluid present in the environment of use. Otherrepresentative compositions for forming first section 12a such asvinylidene chloride copolymers and terpolymers acrylon; trile polymers,halogenated polymers and polycarbonates are discussed in U.S. Pat. No.5,057,318, incorporated by reference herein.

Wall section 12b surrounds that portion of internal compartment 18 thatcontains expandable driving member 25 for expanding and for occupyingspace in compartment 18 for delivery of an active agent formulation fromdelivery system 10. Second wall section 12b is permeable to the passageof fluid and it is substantially impermeable to the passage of otheringredients contained in delivery system 10. The thickness and thesurface area of the second wall section 12b contribute to the rate ofpassage of fluid through the membrane second wall section.

Typical semipermeable materials, flux enhancers and plasticizers forforming wall 12b are known in the art, and are described in detail inrelated application, Ser. No. 08/269,596, and in U.S. Pat. No. 5,057,318already incorporated by reference.

If the material used in the formation of the wall section surroundingthe osmotic driving member, for example wall section 12b, is not asstrong as the material used in the formation of the portion surroundingthe active agent 6, for example first wall section 12a, then the weakermaterial is preferably positioned or disposed to the inside or insertedwithin the stronger material. For example, if cellulose acetate butyrateis used for the portion surrounding the osmotic driving member andpolypropylene is used to surround the active agent 7, then the celluloseacetate butyrate wall is preferably on the inside of the polypropylenewall.

Referring again to FIG. 1, compartment 18 comprises an active agentformulation 7, which active agent formulation 7 comprises an activeagent 7a, identified by dots, and a pharmaceutically acceptable carrier21, identified by wavy lines. The pharmaceutically acceptable carriermay include more than one ingredient, such as a buffer 22, identified byhorizontal dashes; a pharmaceutically acceptable viscosity modulatingvehicle 23, identified by vertical lines; a pharmaceutically acceptablesurfactant 24, identified by slanted lines; and other formulationingredients, as are known in the art. Delivery device 10 in itscompartment 18 can also comprise pharmaceutical carrier 21. Carrier 21may optionally include viscosity modulating vehicles (23), buffers (22),surfactants (24), dyes, and other additives known in the art, examplesof which are disclosed in U.S. Pat. No. 5,034,229 and 5,135,123 tocomprise the active agent formulation 7.

One class of fluid-sensitive agents that are presently preferred fordelivery from the devices of the present invention are growth factors,including bovine somatotropin and analogues and derivatives thereof. Thedevices of the present invention provide a means for delivering aneffective amount of an active agent for causing increased productivity,such as, in the case of the somatotropins, a higher feed conversionefficiency, improved carcass quality, higher than normal rate of animalweight gain, and increased milk production.

In a presently preferred embodiment, the active agent is bovinesomatotropin, in an amount of from about 25% to about 60% by weight (wt%) of the active agent formulation 7, preferably from about 30 wt % toabout 45 wt %. In addition, a salt such as NaCl or KCl may be present inamounts of 1-4% by weight to assist stabilizing the state offormulation.

Wall section 12b surrounds, an expanding driving member 25 optionallycomprising members 25a-f. Expandable driving member 25 expands inresponse to fluid imbibed across wall 12b and optionally comprises anosmagent homogeneously or heterogeneously blended with binder.

The expandable driving member 25, initially surrounded by second wallsection 12b and operable for pushing the active agent formulation 20from delivery device 10 comprises, in a presently preferred embodiment,an osmopolymer. The expandable driving member 25 in another preferredembodiment comprises an osmagent. The expandable driving member 25 yetin another preferred embodiment comprises an optional osmagent dispersedwithin the osmopolymer. Osmagents and osmopolymers are known to the artin U.S. Pat. Nos. 3,865,108, 4,002,173, 4,207,893, 4,327,725, 4,612,008,5,034,229, and 5,135,123 for example, the disclosures of which areincorporated by reference herein.

In a presently preferred embodiment, delivery device 10 comprises aplurality of expandable driving members 25a-f initially housed in secondwall section 12b. This configuration is merely illustrative and theremay be any number of driving means present. Generally, there are fromone to six expandable driving means; however, this number is notcontrolling. The expandable driving members in a presently preferredembodiment are formed as depots or layers and comprise like or unlikecompositions. For example, driving means 25a-f can be made as tabletscomprising like osmopolymers or like osmagents, or they can compriseunlike osmopolymers or unlike osmagents, or one or more of the memberscan be a composition comprising an osmopolymer together with anosmagent. The members can be the same or they can be different.

The terms "exit means" and "exit passageway", as used herein, comprisemeans and methods suitable for the metered release of the active agent 6from compartment 18 of delivery device 10. This includes maintainingsufficient efflux or outward velocity of the active agent to prevent aninward flow of fluid from the external environment to dilute the activeagent formulation in the portion of the compartment comprised by thefirst wall section. The exit passageway 13 includes at least onepassageway, orifice, or the like, through first wall section 12a forcommunicating with compartment 18. The expression "at least onepassageway" includes aperture, orifice, bore, pore, porous elementthrough which the agent can migrate, hollow fiber, capillary tube,porous overlay, porous insert, and the like. The expression alsoincludes material that gets discharged, erodes or is leached from thewall in the fluid environment of use to produce at least one passagewayin delivery device 10. Passageways and materials, equipment and methodsfor forming passageways are disclosed in U.S. Pat. No. 5,034,229.

Movable partition 26, positioned between the beneficial agentcomposition and the expandable driving member is a means for (1)maintaining the separate identity of the beneficial agent compositionand the driving member, for (2) transmitting the force generated by thedriving member against the beneficial agent composition, and (3) forsubstantially restricting the passage of fluid between the beneficialagent composition and the driving member. Representative materialsinclude waxes, elastomeric pistons, and polymer compositions, examplesof which are disclosed in U.S. Pat. No. 5,034,229 and related case U.S.Ser. No. 08/269,569.

In a preferred embodiment, the device 10 includes a delivery devicecharacterized by a shortened start-up time, e.g., from 50 days to lessthan 21 days. It was discovered that as the fluid was imbibed throughthe semipermeable wall section 12b, rather than expanding longitudinallywithin the internal compartment 18 and forcing the active agent 7 outthrough the exit passageway 13, the expandable driving member 25expanded, in part, radially outward. This extended the startup time ofthe delivery device mby diverting the expansion radially outward,reducing the amount of longitudinal expansion and thus the push of themember 25 against the partition 26 or directly against the active agent6. Responsive to this problem, to reduce the radial swelling of thesemipermeable wall section, the rigidity of the wall was increased byreducing the amount of plasticizer in the wall composition. In oneembodiment, to increase the wall's rigidity, the semipermeable wallsection composition was comprised of 90% Cellulose acetate butyrate and10% tributylcitrate. This compositional change had a significant effecton the semipermeable wall section strength, reducing the start-up timeto less than 21 days by minimizing the radial swelling of the wallsection.

As illustrated in FIGS. 1-6, a locking coupling 200 between the firstand second wall sections provides a strengthened joint therebetween. Thelocking coupling is preferably used when the fluid permeable wallsection is formed of material having a greater than or equal to the hoopstrength or radial expansion of an 85% CAB and 15% TBC fluid permeablewall section composition. These embodiments are particularly useful indevices having shortened start-up times and are thus subjected toadditional structural distress. For example, when the device hasexpelled all of the active agent formulation and the partition layerreaches the end cap, fluid continues to be drawn through the fluidpermeable wall section and a build-up of pressure ensues within thedevice. The pressure will continue to build within the internalcompartment 18. When the yield strength of the components is exceeded,the material failure of the device may occur. Those in the art willrecognize various factors which contribute to the yield strength of adevice include the materials used (the differences between CAB/TBCratios and the effect upon the materials characteristics), physicalparameters such as thickness, area; and/or the expansion fo the drivingmember. To adjust for this additional pressure, especially when 90/10CAB/TBC wall formulations were utilized, wall sections 12a and 12b wereconfigured to interlock mechanically with one another.

A preferred embodiment of the locking coupling 200 is illustrated inFIG. 1. In this embodiment, the locking coupling 200 is an annular snapjoint which includes a coupling projection 202 formed on the outersurface 203 of second wall section 12b for receipt within annular jointdepression 204 defined within the inside surface 208 of first wallsection 12a. Coupling projection 202 has a gently sloped inserting face210 and a sharply sloped, nearly perpendicular, retaining face 212.

As best shown in FIG. 2, a forward angle 220 is defined by theperpendicular to the outside surface 203 of the second wall section 12band the surface of the inserting face 210. A large forward angle, i.e.,a gentler slope, that is more parallel to the outside surface 203 of thesecond wall section 12b, will provide low resistance to insertion of themale telescoping second wall section 12b, into female first wall section12a and into a mechanically engaged position. In one preferredembodiment, the forward angle 220 is 73°. A back angle 222 is defined bythe perpendicular to the outside surface 203 of the second wall section12b and the surface of the retaining face 212. A sharply sloping (moreperpendicular to the longitudinal axis) back angle 222 resists withdrawof the male wall section 12b from engagement with the female wallsection 12a and yields a stronger joint. A more gently sloped back angle222 provides for a weaker joint, but requires less force to withdraw thewall section off the core pin after molding. A back angle between 10-30°is easily molded and still gives a sufficiently strong joint. A 10-20°is preferred and 15% back angle 222 is the most preferred since theseangles provide inherently better joint strength characteristics. Stillreferring to FIG. 2, an adhesive receiving compartment 224 is definedbetween the first wall section 12a and the second wall section 12b,e.g., between the projection and the receiving depression, for receiptof an adhesive 226 therein. Representative adhesives include those thatprovide a strong mechanically and hydrostatically intact seal when theyare bonded together, an adhesive, such as a pressure-sensitive contactadhesive, a moisture-curing adhesive, an ultraviolet-curing adhesive orthe like are suitable for the purposes of this invention. Preferably theadhesive is a cyanoacrylate adhesive having a low-enough viscosity towick into the joint and form a secure bond. A cyanoacrylate adhesivehaving the same qualities and characteristics as that sold by Loctite ofNewington, Conn. under the brand name Loctite 4014 Prism Medical Grade.

The strength of the locking coupling of this embodiment is also afunction of the depth of joint depression 204. Joint strength increasesas the depression depth increase. The maximum depth is dependent uponthe permissible strain of the second wall section material 12b. Forexample, the permissible strain for polypropylene is approximately 70%of its yield strength. To remain in the elastic region of thestress-strain curve for polypropylene, an undercut depth of 0.010 inches(0.0254 cm) provides sufficient joint strength without compromising theintegrity of the material.

Another embodiment of the locking coupling 200 is shown in FIG. 3. Inthis embodiment the locking coupling is a screw joint, with theprojection 230 preferably as a helically, outwardly extending threadedportion 226 of the second wall section 12b, formed on the outer surface203 thereof. The projection 230 threadingly engages with a jointdepression 238, for example, a threaded portion of the first wallsection 12a. The helical receiving depression 238 is defined within theinside surface 208 of the female first wall section 12a for threadedengagement with the projection 230. The threaded portion of the firstand second wall sections define a compartment 238 for receiving anadhesive therebetween. The width of the helical receiving groove iswider than the projecting threads to define helical adhesive receivingcavity 238. This provides additional strength to the joint. The adhesiveis injected into the cavity before twisting and seating of the fluidpermeable wall section 12b.

As best shown in FIG. 4, another embodiment of the locking joint 200 isillustrated. In this embodiment, the locking joint is a bayonet jointwhich includes a projecting tab 240. Projecting tab 240 extends radiallyoutward from the outside surface 203 of the male second wall section12b. As shown in FIG. 5, receiving depression 242, sized to receive theprojecting tab shown in FIG. 4, includes a first receiving portion 234and a second receiving portion 236. First receiving portion 234 providesa means so that the projecting tab 240 is received within depression242, when the male second wall section 12a telescopes longitudinallyinto the female first wall section 12b. Second receiving portion 236 isperpendicular to the first receiving portion 234 so that rotation of theinserted wall section about the longitudinal axis couples the wallsections.

Another embodiment of the locking joint 200 is illustrated in FIG. 6. Inthis embodiment, the locking joint 200 is a tabular snap fit joint. Inthis embodiment, a plurality of projections 250 extends outward from theoutside surface 203 of second wall section 12b. The projection 250 isreceived within receiving depressions 242 defined within the insidesurface 208 of the female first wall section 12a. This embodiment issimilar to the annular snap joint embodiment of FIGS. 1 and 2 exceptthat instead of an annular projection extending entirely around theouter surface 203 joint in this embodiment, the projections 250 andreceiving depression 242 do not extend entirely about the circumferenceof the wall sections. In one preferred embodiment three tabs areequidistantly distributed about the circumference.

The implant can be implanted into the peritoneal cavity using animplanter. Generally, an implanter comprises a tubular member with acentral longitudinal axial bore, a pointed, elongated, annular concavelybeveled implanting end and an implant-charging end. The implanting endand the charging end communicate through a bore. A plunger adapted to beremovably inserted in the bore is designed for slidable movement thereinfor applying the necessary force for implanting the implant.Alternatively, the implant can be surgically or subcutaneously implantedin the peritoneal cavity.

Delivery device 10 can be manufactured by standard manufacturingtechniques. In one process, the first wall section 12a and the secondwall section 12b are independently injection molded or extruded into thedesired shape. Then, the first wall section 12a is filled with theactive agent composition. The second wall section 12b is filled with anexpandable driving member or members, and the piston 29 is next addedthereto in layered arrangement. Optionally, the piston 29 may be addedto the first wall section 12a after filling the wall section with activeagent, in addition to, or instead of, the partition layer added tosecond wall section 12b. Next, the two sections at their open ends areslid together.

The delivery device of the present invention can be manufactured fordelivering numerous active agents, including drugs, at a controlled rateto a presently preferred biological environment of use such aswarm-blooded animals, including humans; ruminants, such as bovines andsheep; porcines, such as hogs and swine; horses; and the like. Thedelivery devices provide for high loading of an active agent and for itsimproved delivery in beneficially effective amounts (that is, amountsthat provide a beneficial effect) over time. It is to be understood thatthe delivery devices can take a wide variety of shapes, sizes and formsadapted for delivering active agents to environments of use. Forexample, the devices manufactured as delivery devices can be used fordispensing an active agent in the anal-rectal passageway, in thecervical canal, as an artificial gland, in the vagina, as a subcutaneousor intraperitoneal implant, and the like. The delivery devices can beused in hospitals, nursing homes, outpatient clinics, sickrooms,veterinary clinics, farms, zoos, and other environments of use.

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, the drawings and the accompanying claims.

While there has been described and pointed out features of the inventionas applied to presently preferred embodiments, those skilled in the artwill appreciate that various modifications, changes, additions andomissions in the devices illustrated and described can be made withoutdeparting from the spirit of the invention.

What is claimed is:
 1. An osmotic delivery device for dispensing anactive agent to an environment of use, the delivery device comprising:afirst wall section; a second wall section; an interlocking couplingbetween the first and second wall sections, the coupled sectionsdefining an internal compartment; an active agent and an expandabledriving member enclosed within the compartment formed by the coupledfirst and second wall sections; and an exit passageway in the first wallsection for delivering the active agent to the environment of use. 2.The device of claim 1, further comprising a movable partition betweenthe active agent and the expandable driving member.
 3. The device ofclaim 1, wherein the first wall section comprises a fluid impermeablematerial and the second wall section comprises an fluid permeablematerial.
 4. The device of claim 1, wherein the interlocking couplingcomprises a projection received within a depression.
 5. The device ofclaim 4, wherein the projection and the depression define an adhesivereceiving compartment therebetween.
 6. The device of claim 4, whereinthe projection comprises a threaded portion of the first wall sectionthat threadingly engages with the depression that comprises a threadedportion of the second wall section.
 7. The device of claim 6, whereinthe threaded portion of the first and second wall sections define acompartment for receiving an adhesive therebetween.
 8. The device ofclaim 4, wherein the projection comprises a gently sloping insertingface and a sharply sloping retaining face.